Adult and neonatal pulmonary and systemic vascular disease is a common clinical problem. These vascular diseases include pulmonary and/or systemic hypertension, atherosclerosis, post-angioplasty re-stenosis, post-transplant vasculopathy, diabetic vasculopathy, peripheral vascular disease, vasculitis, and capillaritis. They are complicated by cardiac hypertrophy, dysfunction, or failure. These clinical problems characteristically include alterations in vascular structure, such as abnormalities in vessel wall thickness and/or vessel formation and/or obliteration, and alterations in vascular tone, such as abnormal contractile response to agonists. Myocardial hypertrophy, dysfunction, or failure are also often observed. These disease processes also cause important vascular cell responses in smooth muscle cells, adventitial fibroblasts, and endothelial cells that contribute to the disease process, including hypertrophy, proliferation, migration, matrix protein synthesis, permeability, and contraction. Inflammatory cell recruitment and activation is also though to be important in the pathogenesis of vascular disease.
Among these diseases is chronic hypoxic pulmonary hypertension (PHTN), which results from structural remodeling and abnormalities of vascular tone (Reeves and Herget, 1984; Haworth, 1993). The alteration in vascular structure results from changes in cellular hypertrophy, proliferation, apoptosis, differentiation, migration, permeability and matrix protein synthesis (Meyrick and Reid, 1979; Rabinovich, et al., 1981; Jones, et al., 1984; Stenmark, et al., 1987). The pulmonary hypertensive process has been observed in several species, including adult mice (Hales, et al., 1983; Klinger, et al., 1993; Steudel, et al., 1998; Fagan, et al., 1999).
The cellular and molecular mechanisms by which the pulmonary hypertensive process occurs are still poorly understood. However, it has been observed that protein kinase C (PKC) is involved in many of the vascular cell responses that contribute to the pulmonary hypertensive process (Komero, et al., 1991; Nishizuka, 1992; Haller, et al., 1994; Ways, et al., 1995). PKC is an important signal transduction pathway involving a family of at least 11 related intracellular kinases. One isozyme in particular, PKC-.alpha., has been implicated in vascular cell responses to hypoxia (Goldberg, et al., 1997; Dempsey, et al., 1997, 1998; Xu, et al., 1997). On the basis of this assertion, as well as earlier studies, the PKC pathway has been presumed to be important in the pathogenesis of chronic hypoxic PHTN (Orton and McMurtry, 1990; Dempsey, et al., 1990, 1991; Xu, et al., 1997). Mechanisms that important here (like PKC) are also thought to play a critical role in other forms of PHTN, systemic vascular diseases, and various lung conditions like asthma, bronchiolitis, interstitial lung disease and lung injury.
It is, therefore, desirable to develop pharmacological strategies to attenuate chronic hypoxic pulmonary hypertension. One such strategy involves the PKC signal transduction pathway. One family of compounds that bind to PKC with high affinity is the bryostatins, a group of macrocyclic lactones isolated from marine bryozoans (Pettit et al., 1982; Kraft et al. 1986). In vitro, it has been found that bryostatin-1 inhibits cell growth and activity of isozymes of PKC, as well as inducing cell differentiation and apoptosis of a variety of transformed cell lines. Its effects on migration and contraction are unknown. Bryostatin-1 induces rapid inactivation and degradation of PKC in a cell-type-and isozyme-specific manner (Lee, et al., 1996, 1997; Blumberg, et al., 1997). In vivo, bryostatin-1 is known to accumulate in the lung in high concentrations. It is currently being tested in NCI-sponsored clinical trials for treatment of several types of malignancies (Zhang, et al., 1996; Caponigro, et al., 1997; Weitman et al., 1999).